What is Amyloidosis2020-08-12T08:24:20+00:00

What is Amyloidosis?

  • Amyloid is a deposit where the native protein has misfolded into an antiparallel β-sheet secondary structure to form insoluble fibrils
  • Amyloidosis is any disease caused by amyloid that has aggregated in extracellular tissue causing disruption and impairment of organ structure and function1
  • Amyloidosis can be due to deposition to any one of 36 different proteins
  • This part of the website covers definitions, nomenclature, molecular pathogenesis, amyloidosis groupings and epidemiology
  • The field of amyloid medicine is constantly evolving. As medical science advances, new types of amyloid continue to be discovered as does new effective directed therapies
  • Note: This website does not discuss the neurodegenerative forms of amyloidosis as there is little diagnostic and clinical overlap between the neurodegenerative forms and the other amyloid types. Examples of neurodegenerative forms of amyloid include Alzheimer’s disease (Aβ), cerebral amyloid angiopathy (Aβ) and prion related amyloid

What is Amyloidosis?

Introduction

KEY POINT

  • Amyloid is a description for a product where the native protein has misfolded into an antiparallel β-sheet secondary structure to form insoluble fibrils
  • Amyloidosis is any disease associated with deposits of amyloid fibrils, arising from 36 different proteins, that have aggregated in extracellular tissues resulting in the disruption and impairment of organ structure and function
  • Amyloid is a “catch-all” term for a pathological deposited proteinaceous material recognised by certain properties and appearance
    • It is comprised of misfolded insoluble fibrils that have been constructed from (usually) endogenous/physiologic soluble proteins
    • Amyloid fibrils are extremely strong, highly ordered and organized fibres that can be formed by a large number of proteins and peptides
      • Amyloid fibrils have been described as having a similar tensile strength to steel and this is a property that they share with their structural cousin silk2
    • Amyloid deposits can be physiological (e.g. enamel in teeth) or pathological (e.g. in amyloidosis)
  • Amyloidosis is any disease associated with deposits of amyloid fibrils that have aggregated in the extracellular tissues resulting in disruption and impairment of organ structure and function
    • Amyloidosis is the term used when aggregated proteins are definitely causal and not secondary phenomena
  • Each type of amyloidosis disorder is associated with a particular protein or peptide
    • In humans, amyloid can be made from 36 proteins and most of these proteins are endogenous proteins1
    • However, fortunately for clinicians, >95% of patients diagnosed in AAN Clinics have disease due to just 3 proteins: Immunoglobulin light chain (AL), transthyretin (ATTR) and Serum Amyloid A (AA).
    • New amyloidogenic proteins continue to be identified at a slow but steady rate as medical technology advances
  • All types of amyloid deposits, no matter their constituent protein or type are identified in tissue using the Congo Red stain
    • For a positive result, Congo red stains amyloid deposits salmon pink and these deposits then exhibit apple green birefringence and dichroism effects under polarised light
  • Amyloidosis is a heterogenous disorder with the amyloid made of differing proteins, created by disparate amyloidogenic mechanisms and with differing clinical phenotypes, prognosis and treatments. Table. Amyloid Fibril proteins and their precursors

Nomenclature

KEY POINT

  • The nomenclature system for the amyloid fibril protein is based on the amyloid fibril precursor protein
  • The nomenclature system for the amyloid fibril protein always starts with an “A”, signifying amyloid, followed by letters which are an abbreviated form of the precursor/constituent protein name e.g.
    • Immunoglobulin Light chain amyloid is called AL
    • Transthyretin amyloid is called ATTR
  • The correct term for transthyretin amyloidosis is then ATTR amyloidosis and the correct term for light chain amyloidosis is AL amyloidosis
  • Sometimes the same precursor protein can form amyloid via both acquired and inherited mechanisms. This is most relevant for transthyretin amyloidosis. To distinguish between these two groups;
    • “wt” denotes amyloid derived from wild type protein=physiologic protein e.g. ATTRwt
    • “v” denotes a variant protein created by an amyloidogenic gene e.g. ATTRv signifies transthyretin amyloidosis caused by any inherited amyloidogenic transthyretin gene mutation
  • The medical literature is littered with superseded names for amyloidosis types. These were used before it was recognised that many different proteins can form amyloid deposits. These outdated terms are confusing and inaccurate and should no longer be used;
    • “Primary systemic amyloidosis” is now currently referred to as AL amyloidosis
    • “Secondary amyloidosis” = AA amyloidosis
    • “Senile systemic amyloidosis” = ATTRwt amyloidosis
  • The International Society of Amyloidosis nomenclature committee published the latest amyloid fibril proteins and their precursors in 2018 and an adapted version is presented below1

Table 1. Amyloid Fibril proteins and their precursors. Adapted from Benson M et al1

Fibril protein Precursor protein

Systemic vs

Localised

Acquired vs

Hereditary

Target Organs
AL Immunoglobulin light chain S L A H* Any organ (except CNS)
AH Immunoglobulin heavy chain S L A
AA (Apo) Serum amyloid A S A
ATTR Transthyretin, wild type S A Heart, lung, ligaments, tenosynovium
Transthyretin, variant S H PNS, ANS, heart, eye, leptomeninges
Ab2M β2-Microglobulin, wild type S A Musculoskeletal system
β2-Microglobulin, variant S H ANS
AApoAI Apolipoprotein A I, variants S H Heart, liver, kidney, PNS, tests, larynx, skin
AApoAII Apolipoprotein A II, variants S H Kidney
AApoAIV Apolipoprotein A IV wild type S A Kidney (medulla) and heart
AApoCII Apolipoprotein C II, variants S H Kidney
AApoCIII Apolipoprotein C III, variants S H
AGel Gelsolin, variants S H PNS, cornea
ALys Lysozyme, variants S H Kidney
ALECT2 Leucocyte Chemotactic Factor-2 S A Kidney, liver
AFib Fibrinogen α, variants S H Kidney (primarily)
ACys Cystatin C, variants S H PNS, skin
ABri ABriPP, variants L H CNS CNS CNS CNS CNS CNS CJD, fatal insomnia CJD, GSS syndrome, fatal insomnia
ADan ADanPP, variants L H
Ab Aβ protein precursor, wild type L A
A precursor, variant L H
AaSyn α-Synuclein A
ATau Tau L A
APrP Prion protein, wild type L A
Prion protein, variants L H
Prion protein variant S H PNS
ACal (Pro)calcitonin L A C-cell thyroid tumours
AIAPP Islet amyloid polypeptide L A Islets of Langerhans, insulinomas
AANF Atrial Natriuretic Factor L A Cardiac Atria
APro Prolactin L A Pituitary prolactinomas, aging pituitary
Alns Insulin L A Pharmaceutical amyloid at insulin injection sites
ASPC Lung Surfactant protein L A Lung
AGal7 Galectin 7 L A Skin
ACor Corneodesmosin L A Cornified epithelia, hair follicles
AMed Lactadherin L A Senile aortic media
Aker Kerrato-epithelin L A Cornea, hereditary
ALac Lactoferrin L A Cornea
AOAPP Odontogenic ameloblast-associated protein L A Odontogenic tumours
ASem1 Semenogelin 1 L A Vesicula seminalis
AEnf Enfurvitide L A pharmaceutical amyloid at injection sites
ACatK Cathepsin K L A Tumour associated

Key: A=acquired, ANS= autonomic nervous system, CNS= central nervous system, H= hereditary, L= localised, PNS= peripheral nervous system, S=systemic

* AL amyloidosis is an acquired disorder. There is however one family described in the literature who have inherited AL. This family do NOT have a measurable monoclonal light chain). Benson M et al. Hereditary systemic immunoglobulin light-chain amyloidosis. Blood. 2015:125 (21);3281-3286.

Molecular Mechanism of Amyloid Formation

KEY POINT

  • Amyloidogenesis starts with polymerisation of soluble monomeric peptides and ends with mature insoluble fibrils
  • The triggering pathogenic molecular kinetic factors remains uncertain for many of the amyloid types
  • An important common initial step is a change in the molecular stability of a soluble peptide into a partially unfolded intermediate amyloidogenic monomer
  • These monomers then join into beta pleated sheets (an ubiquitous secondary protein structure) which are the structural backbone of amyloid fibrils
  • Proteolytic breakdown of amyloid fibrils does occur but, when at a slower rate than deposition, fibril accumulation progresses.
  • All amyloid making processes involve polymerisation of soluble monomeric peptides into beta-pleated sheets and these sheets then join to form mature insoluble fibrils
  • However, the initiating pathogenic molecular kinetic/dynamic factors remain unknown for many of the amyloidoses e.g. the following are not fully understood;
    • The age and gender-related in-vivo molecular processes that trigger the formation of ATTRwt
    • The reason why high serum amyloid A (SAA) levels leads to AA amyloidosis in some patients, but not in others, apart from the increased risk associated with homozygous inheritance of the SAA genotype, SAA1α/SA3
  • The triggers for amyloidogenic monomer formation is clearer for some types of amyloidosis e.g.:
    • TTR gene mutations cause production of a TTRv protein which has a greater tendency to misfold
    • An acquired monoclonal plasma cell clone can produce an immunoglobulin light chain protein which by virtue of its amino acid sequence or post-translational modifications, has a greater tendency to misfold
  • All amyloidogenic mechanisms share the following common molecular steps in amyloid formation:
    • A change in the molecular stability of a soluble peptide into a partially unfolded intermediate or amyloidogenic monomer
    • These misfolded monomers join to form
      • ⇒ early species oligomers (dimers, trimers and tetramers) which join together to form
      • ⇒ beta pleated sheets
      • ⇒ protofilaments (up to 200nm in length) which twists together to form
      • ⇒ protofibrils and
      • ⇒ between 2-6 protofibrils twist together into
      • ⇒ an amyloid fibril (around 10 nm in diameter)4
    • There is a nucleation dependent polymerisation propagation model which is also likely “at-play”
    • This model proposes that a nucleus/ ‘seed’/ peptide micelle forms above a critical threshold concentration and that fibrils nucleate within these, elongating by irreversibly binding monomers to their free ends
    • This can be likened to the process of crystallisation and proposes an accelerated method whereby amyloid fibrils can propagate quickly once the amyloid formation process has been initiated
  • All amyloid deposits, no matter the type of constituent precursor protein, also contain serum amyloid P (SAP) and other proteoglycans (e.g. ApoA4, ApoE)
    • The ubiquitous presence of SAP and proteoglycans in all amyloid deposits is capitalised in amyloidosis diagnostics and therapeutic approaches i.e. SAP scan, anti-SAP antibody therapy
  • Proteolytic breakdown of amyloid fibrils by phagocytic cells can occur but, if at a slower rate than deposition, fibril accumulation occurs and progresses. Therapeutic reduction in the production on the causative amyloid protein can lead to gradual clearance of organ deposits. The development of drugs that enhance immune clearance is an important research goal.

Amyloidosis Groupings

KEY POINT

  • It is very important to distinguish between the following groups:
    • Localised versus Systemic amyloidosis
    • and
    • Acquired versus Hereditary amyloidosis

Systemic versus Localised amyloidosis

  • Localised amyloid is a disorder characterised by single organ tissue production and deposition of amyloid.
    • Localised amyloid can consists of a variety of proteins but the most common constitutive protein is immunoglobulin light chain
    • Unlike systemic AL, localised amyloid does not impact on survival nor does it require systemic chemotherapy as local surgical intervention usually provides good disease control
  • Systemic amyloidosis is a disorder where amyloidogenic protein produced at a distant site, circulates in the blood, then deposits as amyloid in the tissues causing organ failure and impacting on survival
    • Therapies are required to switch off amyloid production in this group of amyloidosis and many approaches have been found already e.g.:
      • Stopping the production of the amyloid precursor protein such as chemotherapy in AL amyloidosis and transthyretin antisense therapies in ATTR
      • Molecularly targetted therapies such as TTR molecule stabilisers (e.g. tafamidis and“AG10”) which can stop circulating TTR tetramers from dissociating into the monomers that go on to form ATTR

Acquired versus Hereditary Amyloidosis

  • Acquired amyloidoses are not caused by inherited genetic mutations
  • Hereditary amyloidosis is caused by a germline gene mutation and there are >150 gene mutations that are known to create variant amyloidogenic proteins
    • The vast majority of amyloidogenic germline mutations occur in the TTR gene
      • >140 TTR gene mutations can cause ATTRv amyloidosis
      • Rarer amyloidogenic mutations can occur in genes encoding fibrinogen A alpha, apolipoprotein, gelsolin and lysozyme proteins
    • The genetic mechanisms and inheritance patterns share the following common features
      • Single base substitution
      • Autosomal dominant inheritance pattern
      • Incomplete penetrance
      • Variable phenotype (even within the same gene mutation)
      • Family history is not always present except in endemic populations

Epidemiology

KEY POINT

  • Although amyloidosis is widely considered to be a rare entity some types are actually common
  • Amyloidosis is widely perceived as rare disorder yet certain types of amyloidosis are common i.e.
    • It has long been known that ATTRwt amyloid deposits are a common age-related phenomenon. In a Finnish autopsy study 25% of those over 85 years of age had ATTRwt deposits on histopathologic analysis5
    • ATTRwt is now the commonest type of amyloidosis seen in AAN centres
  • In terms of the incidence of all the amyloidoses:
  • In Australia, the estimated incidence of amyloidosis based on case ascertainment from histopathology reports was approximately 12 cases per 1 000 000 persons per year6
  • Such estimated minimum incidence rates under-report the “true” incidence of amyloidosis as not all;
    • cases are recognised at the time of death
    • types of amyloid are identified by biopsy
  • From another prospective, ATTRwt constitutes the majority of referrals to AAN clinics and this is expected to increase in the era of the “non biopsy diagnosis of transthyretin cardiac amyloidosis. For one AAN clinic between 2017 and 2019, the most common types of amyloidoses referred between 2017 to 2019 was as follows 7
    • ATTRwt 45%
    • AL 30%
    • Localised 12%
    • ATTRv 5%
    • AA 3%
    • Other 3%

Table 2: Amyloid Fibril proteins and their precursors in order of frequency as seen in an AAN clinic 2017-20197

Fibril protein Precursor protein % AAN referrals Systemic Vs Localised Acquired

Vs Hereditary

Target Organs
ATTR Transthyretin, wild type 45 S A Heart, lung, ligaments, tenosynovium
AL Immunoglobulin light chain (systemic) 30 S A H Any organ (except CNS)
AL Immunoglobulin light chain (Localised) L A Mucosal, glandular tissue

Note: NEVER in vital organs without mucosal tissue such as heart, kidney, nerves, liver, spleen

ATTR Transthyretin, variant 10 S H PNS, ANS, heart, eye, leptomeninges
AA (Apo) Serum amyloid A 3 S A Any organ (except CNS)
ALECT2 Leucocyte Chemotactic Factor-2 1 S A Kidney, liver
ASem1 Semenogelin 1 1 L A Vesicula seminalis
AIns Insulin 1 L A Iatrogenic/pharmaceutical at insulin injection sites
AFib Fibrinogen α, variants <1 S H Kidney (primarily)
ALys Lysozyme, variants <1 S H Kidney
AApoAII Apolipoprotein A II, variants <1 S H Kidney
AApoAI Apolipoprotein A I, variants <1 S H Heart, liver, kidney, PNS, tests, larynx, skin
AGel Gelsolin, variants <1 S H PNS, cornea
AH Immunoglobulin heavy chain <1 S A Any organ (except CNS)
Aβ2M β2-Microglobulin, wild type <1 S A Musculoskeletal system

Key: A=acquired, ANS= autonomic nervous system, CNS= central nervous system, H= hereditary, L= localised, PNS= peripheral nervous system, S=systemic